Therapeutic use of regulatory T cells for graft‐versus‐host disease

Elias, Shlomo; Rudensky, Alexander Y.

doi:10.1111/bjh.16157

Cited by 46 publications

(33 citation statements)

References 108 publications

(136 reference statements)

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“…They have shown positive results in preclinical trials and their ability to ameliorate GVHD is under investigation. However, this approach requires standardization of Treg expansion methods and doses [39,40]. Inducible Tregs can readily be generated, but controversial preclinical ndings and phenotype instability have hampered their translation to the clinic [18].…”

Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host diseas with combination of regulatory T cells

Park

Baek

Kim

et al. 2020

Preprint

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Background: Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting. Methods: We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysisResults: We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3+Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset.Conclusions: Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.

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Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host diseas with combination of regulatory T cells

Park

Baek

Kim

et al. 2020

Preprint

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“…Treg cells are negatively associated with the development of GvHD and other inflammatory diseases including arthritis, irritable bowel syndrome, atopic dermatitis, and psoriasis [103,104]. In mouse models of GvHD, both natural and induced Treg cells suppress the proliferation of conventional T cells, thereby preventing GvHD while preserving the GvL effect [105,106].…”

Section: Effect Of Hdac Inhibitors On Donor T Cell Activation and Difmentioning

confidence: 99%

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Kim

Santhanam²,

Lim

et al. 2020

IJMS

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.

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“…Early clinical trials with iT reg infusion in patients have shown promising results for aGVHD prevention (178)(179)(180), [reviewed in (164)]. Nevertheless, the major problem with the clinical transfer of T reg is the difficulty of reaching a sufficient number of T reg with good purity to infuse and of ensuring that the transferred cells persist and retain their tolerogenic properties in the inflammatory context of aGVHD (181).…”

Section: Strategies Aimed At Promoting Immune Tolerancementioning

confidence: 99%

How to Make an Immune System and a Foreign Host Quickly Cohabit in Peace? The Challenge of Acute Graft-Versus-Host Disease Prevention After Allogeneic Hematopoietic Cell Transplantation

et al. 2020

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Allogeneic hematopoietic cell transplantation (alloHCT) has been used as cellular immunotherapy against hematological cancers for more than six decades. Its therapeutic efficacy relies on the cytoreductive effects of the conditioning regimen but also on potent graft-versus-tumor (GVT) reactions mediated by donor-derived immune cells. However, beneficial GVT effects may be counterbalanced by acute GVHD (aGVHD), a systemic syndrome in which donor immune cells attack healthy tissues of the recipient, resulting in severe inflammatory lesions mainly of the skin, gut, and liver. Despite standard prophylaxis regimens, aGVHD still occurs in approximately 20-50% of alloHCT recipients and remains a leading cause of transplant-related mortality. Over the past two decades, advances in the understanding its pathophysiology have helped to redefine aGVHD reactions and clinical presentations as well as developing novel strategies to optimize its prevention. In this review, we provide a brief overview of current knowledge on aGVHD immunopathology and discuss current approaches and novel strategies being developed and evaluated in clinical trials for aGVHD prevention. Optimal prophylaxis of aGVHD would prevent the development of clinically significant aGVHD, while preserving sufficient immune responsiveness to maintain beneficial GVT effects and immune defenses against pathogens.

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Therapeutic use of regulatory T cells for graft‐versus‐host disease

Cited by 46 publications

References 108 publications

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host diseas with combination of regulatory T cells

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host diseas with combination of regulatory T cells

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

How to Make an Immune System and a Foreign Host Quickly Cohabit in Peace? The Challenge of Acute Graft-Versus-Host Disease Prevention After Allogeneic Hematopoietic Cell Transplantation

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